A Single-dose, Two-Period Crossover Bioequivalence Study Comparing Two Liraglutide Formulations in Healthy Chinese Subjects.

Liraglutide, a glucagon-like peptide 1 receptor agonist, is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. The original liraglutide products are costly, which limits patient access to this therapeutic treatment. Herein, a biosimilar was developed that is highly similar to the reference drug in molecular structure and bioactivity, and is expected to have similar pharmacokinetic (PK) and safety profiles in clinical studies. This study aimed to primarily evaluate the bioequivalence of 2 liraglutide formulations and secondarily assess their safety in healthy Chinese subjects following a single-dose subcutaneous injection. Thirty-two healthy volunteers were recruited in this randomized, open-label, single-dose, 2-period crossover bioequivalence study (ChiCTR2100043348). The geometric mean ratios (GMRs) of the test drug to the reference drug (T/R) and corresponding 90% confidence intervals (CIs) for maximum concentration (Cmax ) and the area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-t ) were estimated using a mixed-effects model, and bioequivalence was determined to have been achieved if the 2-sided 90%CI fell within the predefined range of 80%-125%. PK parameters were comparable between T and R, with GMRs of T/R for Cmax and AUC0-t being 105.7% and 107.7%, respectively, the 90%CI of which met the acceptance criteria for bioequivalence. We also observed a similar and favorable safety profile in the T and R arms, with adverse events being predominantly mild in severity and of gastrointestinal origin. Our findings indicate that the test drug is safe and well tolerated, bioequivalent to the reference drug, and warrants further testing in a phase III clinical trial.

A phase I, single-sequence, open-label study to evaluate the drug-drug interaction between hetrombopag and cyclosporine in healthy Chinese subjects.

AIMS: This study aims to evaluate the drug-drug interaction (DDI) between hetrombopag and cyclosporine in healthy Chinese subjects. METHODS: Twenty-six eligible subjects enrolled in this single-centre, single-sequence, open-label, DDI study with 3 treatment periods, receiving 5 mg hetrombopag once on Day 1, 100 mg cyclosporine twice daily from Day 11 to Day 15 and 5 mg hetrombopag + 100 mg cyclosporine on Day 16. Serial blood samples were collected for pharmacokinetic evaluation. Adverse events were monitored throughout the study. RESULTS: The plasma hetrombopag geometric mean ratios (90% confidence interval) of maximum plasma concentration, area under the plasma concentration-time curve (AUC) from predose to time of last quantifiable sample and AUC to infinity of coadministration of hetrombopag with cyclosporine vs. hetrombopag alone were 95.97% (70.08-131.43%), 105.75% (75.04-149.04%) and 104.19% (74.71-145.32%), respectively, indicating multiple doses of cyclosporine had minimal effects on hetrombopag exposure. The geometric mean ratios (90% confidence interval) of maximum blood concentration and AUC at steady state during a dosing interval for blood cyclosporine of coadministration vs. cyclosporine alone were 100.49% (91.89-109.89%) and 100.81% (107.88-103.82%), respectively, suggesting a single dose of hetrombopag had no impact on the exposure of cyclosporine. Coadministration of hetrombopag with cyclosporine was generally well tolerated. CONCLUSION: No clinically significant DDI was observed when coadministration of hetrombopag with cyclosporine. The results of this study will inform the appropriate use of this combination therapy both in clinical trials and clinical settings.

Identification of the prognostic, diagnostic, and biological significance of the miR-148a-3p/cathepsin A axis in hepatocellular carcinoma.

A comprehensive analysis of the prognostic, diagnostic, and biological significance of miR-148a-3p and cathepsin A (CTSA) in hepatocellular carcinoma (HCC) was performed using bioinformatics algorithms with The Cancer Genome Atlas (TCGA) data. miR-148a-3p and CTSA gene expression in HCC tissues and nontumor specimens was analyzed using TCGA database with R software. CTSA staining analysis was validated using the Human Protein Atlas database. Prognostic, diagnostic, gene set enrichment, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and immune infiltration analyses were implemented using the TCGA database with R software. Based on TCGA data and our cohort populations, CTSA expression was significantly elevated in HCC tissues compared with nontumor specimens. A significant negative correlation between miR-148a-3p and CTSA was observed in the TCGA data and our cohort population. Mechanistically, CTSA was a direct gene target of miR-148a-3p. Both CTSA and miR-148a-3p could serve as prognostic and diagnostic indicators in HCC. miR-148a-3p expression was significantly and negatively correlated with the StromalScore, ImmuneScore, and ESTIMATEScore in patients with liver cancer. miR-148a-3p mimic-mediated apoptosis and the inhibition of HCC cell growth and migration were counteracted by CTSA overexpression. The miR-148a-3p/CTSA axis was implicated in immune cell infiltration and carcinogenesis of HCC. miR-148a-3p and CTSA might be prospective molecular targets to enhance the potency of immunotherapy in HCC.

Long noncoding RNA TSLNC8 enhances pancreatic cancer aggressiveness by regulating CTNNB1 expression via association with HuR.

Pancreatic cancer (PC) is one of the most lethal malignancies worldwide. Tumor suppressor long noncoding RNA on chromosome 8p12 (TSLNC8) is a newly identified long noncoding RNA (lncRNA) and play an important role in human cancers. However, the function and molecular mechanism of TSLNC8 in PC progression remain to be elucidated. Our results showed a significant increase of TSLNC8 expression in PC tissues and cell lines. Upregulation of TSLNC8 expression in PC tissues was closely correlated with TNM stage, distant and lymph node metastasis, and poor prognosis of PC patients. Functional experiments demonstrated that TSLNC8 promoted PC cells proliferation and invasion in vitro, and enhanced PC growth and metastasis in vivo. Mechanistically, TSLNC8 associated with HuR, promoted the binding of HuR with CTNNB1 mRNA and increased the stability of CTNNB1 mRNA, thus activating WNT/ß-catenin signaling pathway. Taken together, our present study revealed that oncogenic lncRNA TSLNC8 positively regulate PC growth and metastasis via HuR-mediated mRNA stability of CTNNB1, extending the understanding of PC pathogenesis regulated by lncRNAs.

Comparison of effects and safety in providing controlled hypotension during surgery between dexmedetomidine and magnesium sulphate: A meta-analysis of randomized controlled trials.

BACKGROUND: Effectiveness of controlled hypotension has been proven in alleviating intraoperative bleeding. Many recent studies emphasized the efficacy of dexmedetomidine and magnesium in providing controlled hypotension during various surgeries. The present meta-analysis of randomized controlled trials (RCTs) was performed to evaluate comprehensively the effects and safety of these two medications. METHODS: Literature search was performed in four databases from inception to April 2019. All RCTs that used dexmedetomidine and magnesium as hypotensive agents were enrolled. The outcomes contained bleeding condition of surgical site, hemodynamic parameters, duration of surgeries, number of patients requiring opioid/analgesia administration, recovery period, and adverse events emerged during surgeries. RESULTS: Ten studies with 663 patients met with our inclusion criteria. The results indicated that both bleeding score and values of mean arterial pressure (MAP) and heart rate (HR) were significantly lower in patients receiving dexmedetomidine (SMD 1.65 with 95% CI [0.90,2.41], P<0.00001) compared to the patients receiving magnesium. The effect in decreasing the necessity of using opioid/analgesia was affirmative in dexmedetomidine group (29.13% with magnesium vs 10.78% with dexmedetomidine), and the condition was more favorable in magnesium group in reducing recovery period (SMD -1.98 with 95% CI [-4.27,0.30], P = 0.09). Compared with magnesium, using of dexmedetomidine was associated with higher incidence of bradycardia but lower incidence of nausea and vomiting. CONCLUSION: Compared with magnesium, dexmedetomidine is more effective to provide promising surgical field condition, favorable controlled hypotension, and less necessity of opioid or analgesia administration. But long recovery period and high-probability bradycardia should be deliberated.

FXYD6 overexpression in HBV-related hepatocellular carcinoma with cirrhosis.

OBJECTIVE: The aim of this study was to investigate the expression of FXYD domain-containing ion transport regulator 6 (FXYD6) mRNA and protein in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) tissues with cirrhosis, the corresponding paracancerous tissues and the normal liver tissues, and to explore the clinical significance of FXYD6 expression in HBV-related HCC with cirrhosis. METHODS: The FXYD6 mRNA and protein were examined by semi-quantitative reverse transcription polymerase chain reaction and immunohistochemistry, respectively. RESULTS: The FXYD6 mRNA in HBV-related HCC tissues was significantly higher than that in the cirrhosis tissues or that in the normal liver tissues. The positive expression rate of FXYD6 protein was statistically higher in HBV-related HCC tissues than that in HBV-related cirrhosis or that in normal liver tissues. There was no significant correlation between the expression of FXYD6 protein and gender, age, histological differentiation, tumor diameter, tumor number, integrity of tumor capsule or not and alpha fetoprotein (AFP) concentration in serum, but the protein expression was associated with microvascular invasion, pathological stage, and early recurrence after operation within 1 year. CONCLUSION: FXYD6 might be involved in hepatocyte carcinogenesis and tumor progression in HBV-related HCC with cirrhosis and indicated a poor prognosis.

Comparison of the efficacy and safety of remifentanil versus different pharmacological approaches on prevention of etomidate-induced myoclonus: a meta-analysis of randomized controlled trials.

Objective: Myoclonus was considered as one conundrum in etomidate induction, which led to multiple risks during clinical anesthesia. The present study was conducted to compare the efficacy of pretreatment with remifentanil to different pharmacological approaches on reducing etomidate-induced myoclonus. Methods: We searched PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure from the inception to October 2018. Randomized controlled trials comparing remifentanil versus other pharmacological approaches in reducing etomidate-induced myoclonus were eligible to be analyzed. Results: Overall, 13 trials with 1,392 patients met with the inclusion criteria. 1) Pretreatment with remifentanil could reduce the incidence of etomidate-induced myoclonus compared to placebo and fentanyl; few differences were found between the use of remifentanil and the use of midazolam: (incidence of myoclonus: 5.56% with remifentanil vs 71.65% with saline, RR=0.08, with 95% CI [0.05, 0.12], P<0.0001; 3.80% with remifentanil vs 13.33% with fentanyl, RR with 95% 0.31 [0.11, 0.86], P=0.02; 46.00% with remifentanil vs 55.45% with midazolam, RR=0.82, with 95% CI [0.64, 1.06], P=0.13). 2) Compared with placebo, pretreatment with remifentanil could reduce the incidence of mild, moderate, and severe myoclonus; compared with midazolam, patients receiving remifentanil experienced lower occurrence of severe myoclonus; compared with fentanyl, pretreatment with remifentanil associated with significant low occurrence of moderate and severe myoclonus. 3) The outcomes also indicated that pretreatment with remifentanil could prevent excessive hemodynamic changes after endotracheal intubation compared to fentanyl. Conclusions: Pretreatment with remifentanil could be considered as one operative option to reduce both incidence and severity of etomidate-induced myoclonus. Compared with fentanyl, it also provides efficacy in preventing excessive hemodynamic changes after endotracheal intubation. However, the best treatment and the proper prophylactic dosage calls for more high quality evidence with large sample size.

Pretreatment with lidocaine reduces both incidence and severity of etomidate-induced myoclonus: a meta-analysis of randomized controlled trials.

OBJECTIVE: One conundrum that frequently occurs during clinical anesthesia is etomidate-induced myoclonus, which results in multiple risks. The aim of the study was to evaluate systematically the effect of pretreatment with lidocaine on preventing etomidate-induced myoclonus. MATERIALS AND METHODS: The literature search was performed from the inception to April 2018 in PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure. All randomized controlled trials that used lidocaine to prevent etomidate-induced myoclonus were enrolled. The primary outcome included the incidence and severity of etomidate-induced myoclonus. The data were combined to calculate the risk ratio and relevant 95% CI. A meta-analysis was performed following the guidelines of the Cochrane Reviewer's Handbook and the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement. RESULTS: A total of eight studies were enrolled, and the existing evidence indicated that 1) pretreatment with lidocaine can reduce the incidence of etomidate-induced myoclonus (the incidence of myoclonus: 37.6% in lidocaine vs 73.6% in saline, risk ratio =0.46, with 95% CI [0.34, 0.63], P<0.0001); 2) the pretreatment with lidocaine can reduce the incidence of mild, moderate, and severe myoclonus; 3) a dose of pretreatment with lidocaine cannot significantly decrease the duration of myoclonus compared to placebo; 4) the administration of lidocaine produced no effect on the stable hemodynamic parameters and no more additional adverse effects. CONCLUSION: Pretreatment with lidocaine could be served as one effective approach to decrease both the incidence and the severity of etomidate-induced myoclonus, with limited influence on the hemodynamic stability of patients. However, to confirm precise safety and efficacy of such intervention, more high-quality evidence is necessary.

The role of the globular heads of the C1q receptor in paclitaxel-induced human ovarian cancer cells apoptosis by a mitochondria-dependent pathway.

As a mitochondrial membrane protein, globular C1q receptor (gC1qR) can mediate a variety of biological responses. Our study aims to investigate the role of gC1qR in paclitaxel-induced apoptosis of human ovarian cancer cells and to elucidate its potential molecular mechanism. The level of gC1qR was examined using real-time PCR and western blot analyses. Human ovarian cancer cells viability, migration, and proliferation were detected using the water-soluble tetrazolium salt (WST-1) assay, the transwell assay, and H-thymidine incorporation into DNA (H-TdR) assay, respectively. Apoptosis in cells was assessed using flow cytometric analysis. The intracellular reactive oxygen species was estimated by the fluorescence of H2DCFDA and the mitochondrial membrane potential was tested using a JC-1 probe. The expression of the gC1qR gene decreased significantly in human ovarian cancer tissues relative to the surrounding non-neoplastic ovarian tissues. Cells treated with paclitaxel showed increased gC1qR gene expression, cell apoptosis, and mitochondria dysfunction, and the effects on these cells could be abrogated by the addition of gC1qR small-interfering RNA or α-lipoic acid that was used to protect the mitochondria function. In summary, these data support a mechanism that gC1qR-induced mitochondria dysfunction was involved in the paclitaxel-mediated apoptosis of ovarian cancer cells.

Histone deacetylase inhibitor quisinostat activates caspase signaling and upregulates p53 acetylation to inhibit the proliferation of HepG2 cells.

Histone deacetylase inhibitor (HDACi) has been a major target of anticancer agents. Quisinostat (JNJ­26481585), a novel second­generation HDACi, has previously demonstrated antiproliferative activity against non­small cell lung cancer; however, the function of quisinostat in hepatocellular carcinoma (HCC) remains to be elucidated. In the present study, it was revealed that quisinostat suppressed the cell viability of HepG2 cells in vitro and in vivo. Increased cell apoptosis was observed in quisinostat­treated HepG2 cells. The underlying mechanism revealed that quisinostat treatment activates the cleavage of caspase proteins. Furthermore, quisinostat upregulated p53 acetylation at K381/K382 sites by impairing the interaction between histone deacetylase 6 and p53, which resulted in the activation of p53, and triggered cell cycle arrest at the G1 phase. Collectively, the results of the present study demonstrated the antiproliferative effect of quisinostat on HepG2 cells; these results suggest that histone deacetylase may be a promising therapeutic target of HCC.

Expression of EphB6 in ovarian serous carcinoma is associated with grade, TNM stage and survival.

BACKGROUND: Ovarian serous carcinoma (OSC) is the most common ovarian epithelial malignancy. Despite new medical and surgical advances, the overall 5-year survival for OSC remains poor. There is an important need to determine diagnostic and prognostic markers for this disease. Eph receptors are the largest known family of receptor tyrosines characterised in humans. These receptors are involved in the development and progression of various diseases including cancer. EphB6 contains kinase domains that are altered in several conserved amino acids and is catalytically inactive. The aim of the present study was to correlate the immunohistological expression of EphB6 in a cohort of patients with epithelial ovarian tumours with clinicopathological parameters and survival. METHODS: In this study we examined the expression of EphB6 protein in 55 cases of OSC, 24 cases of benign ovarian serous tumours, 37 cases of serous borderline tumours and 20 cases with normal fallopian tubes by immunohistochemical staining with a polyclonal anti-EphB6 antibody. The relationship between EphB6 expression and pathological parameters was analysed. Kaplan-Meier survival function was used to analyse the prognosis. RESULTS: High expression of EphB6 was observed in 100% (20/20) of normal fallopian tube samples, 100% (24/24) of benign epithelial ovarian tumours, 78% (29/37) of ovarian serous borderline tumours and 18% (10/55) of OSCs (p < 0.001). The expression of EphB6 was significantly associated with grade (p < 0.001) and TNM stage (p = 0.017). EphB6 expression was reversely related to Ki-67 (p = 0.021). The survival analysis showed that patients with negative or weak expression of EphB6 protein had a poorer outcome than those with positive expression (p = 0.046). CONCLUSIONS: Our results show that EphB6 is a new biomarker for distinguishing high- and low-grade OSC, and may be a potential prognostic marker in OSCs.

Characterization of Specific Roles of Sodium Channel Subtypes in Regional Anesthesia.

BACKGROUND AND OBJECTIVES: Commonly used local anesthetics (eg, lidocaine) are nonselective in blocking sodium channel subtypes, potentially resulting in adverse events, such as prolonged muscle paralysis and unstable hemodynamics. Subtype-selective sodium channel block might avoid these unwanted adverse effects while preserving desirable anesthetic effects. The contributions of sodium channel subtypes in different components of regional anesthesia are unclear and this study assumed that selective sodium channel subtype block might produce selective nerve block. METHODS: Sciatic nerve block was performed in mice with lidocaine (nonselective sodium channel blocker), tetrodotoxin (TTX, TTX-sensitive sodium channel blocker), and A-803467 (selective Nav1.8 subtype blocker). Tactile sensory, pinprick, and thermal sensory block as well as motor block were evaluated after injection of study drugs. Median effective concentration (EC50) of lidocaine, TTX, and A-803467 as well as their blocking durations were determined. RESULTS: Lidocaine produced regional anesthetic effects including tactile, pinprick, and thermal sensory block as well as motor block, with EC50 [mean, 95% confidence intervals (CIs)] of 4.4 (3.7-5.2), 9.4 (8.0-10.9), 5.2 (4.3-6.2), and 3.7 (3.3-4.2) mmol/L, respectively. Tetrodotoxin produced tactile sensory block and motor block with EC50 (mean, 95% CIs) of 7.7 (6.0-11.0) and 8.3 (7.4-9.8) µmol/L, respectively; whereas A-803467 produced tactile sensory block only, with EC50 (mean, 95% CIs) of 12.6 (11.7-15.6) µmol/L. CONCLUSIONS: Sodium channel subtype selective blockers could induce selective nerve blocks. Tetrodotoxin-sensitive sodium channel subtypes contribute to low-threshold sensory block (eg, tactile) and motor block. Unexpectedly, selective Nav1.8 subtype block induced low-threshold sensory block rather than nociceptive or motor block.

HCN1 Channels Contribute to the Effects of Amnesia and Hypnosis but not Immobility of Volatile Anesthetics.

BACKGROUND: Hyperpolarization-activated, cyclic nucleotide-gated (HCN) subtype 1 (HCN1) channels have been identified as targets of ketamine to produce hypnosis. Volatile anesthetics also inhibit HCN1 channels. However, the effects of HCN1 channels on volatile anesthetics in vivo are still elusive. This study uses global and conditional HCN1 knockout mice to evaluate how HCN1 channels affect the actions of volatile anesthetics. METHODS: Minimum alveolar concentrations (MACs) of isoflurane and sevoflurane that induced immobility (MAC of immobility) and/or hypnosis (MAC of hypnosis) were determined in wild-type mice, global HCN1 knockout (HCN1) mice, HCN1 channel gene with 2 lox-P sites flanking a region of the fourth exon of HCN1 (HCN1) mice, and forebrain-selective HCN1 knockout (HCN1: cre) mice. Immobility of mice was defined as no purposeful reactions to tail-clamping stimulus, and hypnosis was defined as loss of righting reflex. The amnestic effects of isoflurane and sevoflurane were evaluated by fear-potentiated startle in these 4 strains of mice. RESULTS: All MAC values were expressed as mean ± SEM. For MAC of immobility of isoflurane, no significant difference was found among wild-type, HCN1, HCN1, and HCN1: cre mice (all ~1.24%-1.29% isoflurane). For both HCN1 and HCN1: cre mice, the MAC of hypnosis for isoflurane (each ~1.05% isoflurane) was significantly increased over their nonknockout controls: HCN1 versus wild-type (0.86% ± 0.03%, P < 0.001) and HCN1: cre versus HCN1 mice (0.84% ± 0.03%, P < 0.001); no significant difference was found between HCN1 and HCN1: cre mice. For MAC of immobility of sevoflurane, no significant difference was found among wild-type, HCN1, HCN1, and HCN1: cre mice (all ~2.6%-2.7% sevoflurane). For both HCN1 and HCN1: cre mice, the MAC of hypnosis for sevoflurane (each ~1.90% sevoflurane) was significantly increased over their nonknockout controls: HCN1 versus wild-type (1.58% ± 0.05%, P < 0.001) and HCN1: cre versus HCN1 mice (1.56% ± 0.05%, P < 0.001). No significant difference was found between HCN1 and HCN1: cre mice. By fear-potentiated startle experiments, amnestic effects of isoflurane and sevoflurane were significantly attenuated in HCN1 and HCN1: cre mice (both P < 0.002 versus wild-type or HCN1 mice). No significant difference was found between HCN1 and HCN1: cre mice. CONCLUSIONS: Forebrain HCN1 channels contribute to hypnotic and amnestic effects of volatile anesthetics, but HCN1 channels are not involved in the immobilizing actions of volatile anesthetics.

Emulsified halothane produces long-term epidural anesthetic effect: a study in rabbits.

Previous studies have demonstrated that volatile anesthetics could produce local anesthesia. Emulsified isoflurane at 8% has been reported to produce epidural anesthetic effect in rabbits. This study was designed to investigate the long-term epidural anesthetic effect of emulsified halothane in rabbits. In this study, 40 healthy adult rabbits (weighting 2.0-2.5 kg) with an epidural catheter were randomly divided into 4 groups (n=10/group), receiving epidural administration of 1% lidocaine (lido group), 8% emulsified isoflurane 1ml (8% E-iso group), 8% emulsified halothane (8% E-Halo group) and 12% emulsified halothane (12% E-Halo group). After administration, sensory and motor functions as well as consciousness state were assessed until 60 minutes after sensory and motor function returned to its baseline or at least for 180 min. After epidural anesthesia, all the rabbits were continuously observed for 7 days and sacrificed for pathological evaluations. As a result, all the four study solutions produced typical epidural anesthesia. Onset times of sensory and motor function blockade were similar among the four groups (P>0.05). Duration of sensory blockade in 12% E-Halo group (83±13 min) was significantly longer than other groups: 51±12 min in 8% E-Halo group (P<0.01), 57±8 min in 8% E-iso group (P<0.01) and 47±9 min in lido group (P<0.01). Duration of sensory blockade in 8% E-iso group is longer than lido group (P<0.05). Duration of motor blockade in 12% E-Halo group (81±12 min) was also significantly longer than other groups: 40±8 min in 8% E-Halo group (P<0.01), 37±3 min in 8% E-iso group (P<0.01), 37±6 min in lido group (P<0.01). Normal consciousness was found in the rabbits from 8% E-Halo, 8% E-iso and lido groups while there were four rabbits in 12% E-Halo group (4/10) showed a light sedation. For all the rabbits, no pathological injury was found. The present study demonstrates that emulsified halothane produces reversible concentration-dependent epidural anesthesia and at 12% (v/v), emulsified halothane could produce long-term anesthesia without pathological injury.

ROR1 expression correlated with poor clinical outcome in human ovarian cancer.

The receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) is a transmembrane protein belongs to receptor tyrosine kinase (RTK) family. This study aimed to examine the expression of ROR1 in human ovarian cancer and investigate the relationship between its expression and the prognosis of ovarian cancer patients. In this present study, one-step quantitative reverse transcription-polymerase chain reaction (15 ovarian cancer samples of high FIGO stage, 15 ovarian cancer samples of low FIGO stage and nine normal ovary tissue samples) and immunohistochemistry by tissue microarrays (100 ovarian cancer samples and 50 normal ovary samples) were performed to characterize expression of the ROR1 gene in ovarian cancer. Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of ovarian cancer. The results of qPCR and IHC analysis showed that the expression of ROR1 in ovarian cancer was significantly higher than that in normal ovary tissues (all p < 0.05). Survival analysis showed that ROR1 protein expression was one of the independent prognostic factors for disease-free survival and overall survival (both p < 0.05). The data suggest that ROR1 expression is correlated with malignant attributes of ovarian cancer and it may serve as a novel prognostic marker in ovarian cancer.

A temporary stent graft as a new shunt for juxtahepatic vena cava injury.

BACKGROUND: Juxtahepatic vena cava (JHC) injury is difficult to handle because of JHC injury's specific position and liver obstruction. The traditional shunt method initially appeared to be useful but ultimately failed. Simple and effective methods are needed to solve it. METHODS: Firstly, the clinical data, including the computed tomography images, of 120 patients were collected. In addition, a JHC digital model was constructed based on computed tomography images. According to the digital model data, a circulation loop simulating the blood flow in the JHC was established. Secondly, we analyzed the hemodynamics of a JHC shunt with pig blood. Finally, the new shunt was designed based on the data obtained. The shunt consists of a covered stent and transfer device and was tested. RESULTS: The JHC has a three-dimensional cylindrical structure. The mean (SD) length of the retrohepatic vena cava is 78.21 (9.83) mm, which shows correlations with the patient's age and weight (r = -0.343 and 0.271, respectively, p < 0.05). An equation is obtained as follows: retrohepatic vena cava (millimeter) = 71.23 - 0.293 × age (year) + 0.32 × weight (kilogram). The shunt diameters must be 10 mm and 12 mm to maintain the blood pressure difference Point a and Point b at approximately 3.75 mm Hg (5 cm H2O), when the flow rate is 3,000 mL/min and 5,000 mL/min, respectively. The stent graft showed effective hemostasis in tests. However, it failed when the inferior vena cava was pulled harder. CONCLUSION: A temporary stent graft as a new shunt for JHC injury has not been previously reported. It is a combination of both a traditional operation and a simple endovascular technique, which showed effective hemostasis in tests.

Comparison of subarachnoid anesthetic effect of emulsified volatile anesthetics in rats.

Spinal cord is an important target of volatile anesthetics in particular for the effect of immobility. Intrathecal injection of volatile anesthetics has been found to produce subarachnoid anesthesia. The present study was designed to compare spinal anesthetic effects of emulsified volatile anesthetics, and to investigate the correlation between their spinal effects and general effect of immobility. In this study, halothane, isoflurane, enflurane and sevoflurane were emulsified by 30% Intralipid. These emulsified volatile anesthetics were intravenously and intrathecally injected, respectively. ED50 of general anesthesia and EC50 of spinal anesthesia were determined. The durations of general and spinal anesthesia were recorded. Correlation analysis was applied to evaluate the anesthetic potency of volatile anesthetics between their spinal and general effects. ED50 of general anesthesia induced by emulsified halothane, isoflurane, enflurane and sevoflurane were 0.41 ± 0.07, 0.54 ± 0.07, 0.74 ± 0.11 and 0.78 ± 0.08 mmol/kg, respectively, with significant correlation to their inhaled MAC (R(2) = 0.8620, P = 0.047). For intrathecal injection, EC50 of spinal anesthesia induced by emulsified halothane, isoflurane, enflurane and sevoflurane were 0.35, 0.27, 0.33 and 0.26 mol/L, respectively, which could be predicted by the product of inhaled MAC and olive oil/gas partition coefficients (R(2) = 0.9627, P = 0.013). In conclusion, potency and efficacy of the four emulsified volatile anesthetics in spinal anesthesia were similar and could be predicted by the product of inhaled MAC and olive oil/gas partition coefficients (MAC × olive oil/gas partition coefficients).

Roles and mechanism of miR-199a and miR-125b in tumor angiogenesis.

MicroRNAs (miRNAs) have been shown to be involved in different aspects of cancer biology including tumor angiogenesis. In this study, we identified that two miRNAs, miR-199a and miR-125b were downregulated in ovarian cancer tissues and cell lines. Overexpression of miR-199a and miR-125b inhibited tumor-induced angiogenesis associated with the decrease of HIF-1α and VEGF expression in ovarian cancer cells. Moreover, the levels of miR-199a and miR-125b were negatively correlated with VEGF mRNA levels in ovarian tissues. We further showed that direct targets of miR-199a and miR-125b HER2 and HER3 were functionally relevant. Forced expression of HER2 and HER3 rescued miR-199a- and miR-125b-inhibiting angiogenesis responses and Akt/p70S6K1/HIF-1α pathway. This study provides a rationale for new therapeutic approach to suppress tumor angiogenesis using miR-199a, miR-125b, or their mimics for ovarian cancer treatment in the future.

Fibrillar type I collagen matrices enhance metastasis/invasion of ovarian epithelial cancer via ß1 integrin and PTEN signals.

OBJECTIVE: This study investigated the involvement of fibrillar collagen in remodeling extracellular matrices (ECM) and its significant impact on the metastasis/invasion of epithelial ovarian cancer cells via ß1 integrin/phosphatase and tensin homolog (PTEN) signaling. MATERIALS/METHODS: Normal ovarian surface epithelium tissues (n = 13), ovarian cancer tissues (n = 28), ovarian cancer cell lines, and a 3-dimensional model of fibrillar type I collagen that mimicked pathological ECM in vivo were used in the study. We explored the specific mechanisms behind ECM remodeling and the cellular signals that affected the invasion of ovarian cancer cells. RESULTS: The data showed that increased ß1 integrin expression in ovarian cancer cells led to enhance migration/invasion of ovarian cancer cells via regulation of PTEN/protein kinase B (Akt) signal in response to fibrillar type I collagen matrices. Low PTEN activity corresponded to the following: (1) increased PTEN degradation and (2) phosphorylation of PTEN. Decreased protein phosphatase 2A activity was detected in ovarian cancer. Protein phosphatase 2A might play a role in enhancing the progression of ovarian cancer through regulating PTEN/Akt signal. CONCLUSION: These findings indicate that fibrillar type I collagen, by modulating integrin-PTEN/PI3K/Akt signaling pathway in remodeling ECM, is very important in affecting the invasion of aggressive ovarian cancer cells. Moreover, these data provide direct evidence for pathological ECM remodeling and cell signaling networks involved in the invasion of ovarian cancer cells.

DNA ploidy cytometry testing for cervical cancer screening in China (DNACIC Trial): a prospective randomized, controlled trial.

PURPOSE: This randomized, controlled trial was designed to determine whether the DNA cytometry testing is superior to the conventional cytologic testing for mass cervical cancer screening. EXPERIMENTAL DESIGN: After approval by the institutional ethics review boards from three separate screening centers, a total of 23,993 Chinese women ages 20 to 65 years were randomly assigned into one of the two groups: a DNA cytometry testing group (11,999 women) and a cytologic testing group (11,994 women). Each woman underwent the other testing after first attending the assigned screening test. Women with positive results after assigned testing additionally underwent colposcopy and human papillomaviruses detections, and those with cervical precancerous or cancerous lesions received appropriate treatment. Sensitivity and specificity estimates were adjusted for verification bias. Analyses were by intention to treat and per protocol ways. RESULTS: In the cytometric DNA testing group, cervical cancer was diagnosed in 40 subjects, compared with 24 subjects in the cytologic testing group [hazard ratio for the detection of advanced cancer in the DNA cytometry testing group, 0.42; 95% confidence interval (CI), 0.27-0.60]. The sensitivity of the DNA cytometry testing for cervical cancer was 91.7% (95% CI, 64.3-95.8), whereas the sensitivity of cytologic testing was 44.5% (95% CI, 25.2-61.3; P = 0.008). The specificity was 54.1% (95% CI, 31.6-69.0) for DNA cytometry testing and 70.6% (95% CI, 46.8-82.5; P = 0.003) for cytologic testing. The sensitivity of both tests used together was 100%, and the specificity was 91.8%. A total of 187 subjects reported mild to severe adverse events after treatment with positive results in 319 women. CONCLUSIONS: Our results highlight the benefit of the DNA cytometry testing strategy in mass cervical cancer screening with greater sensitivity and positive predicted value than the conventional cytologic testing in developing settings.